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Does deadly diet drug DNP defeat diabetes?

11:30am Friday 27th February 2015content supplied by

"A chemical [DNP] which caused munitions factory workers to lose weight inexplicably in the First World War could cure diabetes," The Daily Telegraph reports. The banned weight loss drug looked effective and safe when given in a modified form to rats bred to have diabetes.

The potential benefits of DNP surfaced in WW1 munitions workers who lost a lot of weight after being exposed to it. DNP sped up their metabolism, leading to rapid weight loss. After being made into a weight loss drug in the 1930s, it was quickly withdrawn, as it was proven highly toxic.

The problem was that it sped up the metabolism to a dangerously high rate, causing a range of serious side effects, and some deaths. Illegal sales of the drug have caused a number of deaths in the UK in recent years.

Researchers at Yale University wanted to see if it was possible to harness DNP's metabolic properties, while removing the toxic effects.

They created a slow-release version of DNP, called CRMP, which improved the way the liver processed fat and improved other measures linked to type 2 diabetes risk in rats. As it delivered DNP at a much lower dose over time, there were no toxic effects.

This is encouraging research that should lead to further studies.

The version of DNP that is available through illegal sales, typically via the internet, is toxic, even in tiny amounts. Do not take it under any circumstances.

What is DNP?

DNP (2,4-Dinitrophenol ) is a combination of compounds that was widely used during the early 20th century in a range of industrial processes.

In 1933, an American researcher discovered that when taken by humans, DNP dramatically sped up metabolism, leading to rapid weight loss. It was subsequently marketed as a weight loss drug. It was quickly withdrawn from the market, however, after it was found to be highly toxic, causing significant side effects, and in some cases, death.

Long-term use can lead to the development of cataracts and skin lesions, and may cause damage to the heart and nervous system. There is also evidence from animal studies that DNP is carcinogenic (cancer-causing) and increases the risk of birth defects.

Where did the story come from?

The study was carried out by researchers from Yale University and was funded by United States National Institutes of Health and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark.

The Daily Telegraph's coverage was factually accurate. They made it clear the research was in rats, but also explained how: "the [research] team is confident that the research would translate to humans and are keen to start trials".

What kind of research was this?

This was an animal study investigating potential new uses for the banned chemical DNP for non-alcoholic fatty liver disease, which in turn, is a major risk factor for type 2 diabetes. Alternatively, both conditions can develop in tandem.

DNP has a murky past. Starting life as an ingredient of explosives in WW1, its potential use as a weight loss drug was recognised in workers handling the agent. They sweated profusely, had sky-high temperatures and lost a lot of weight. In the 1930s, it was sold as a wonder weight loss drug. However, it was quickly withdrawn, because it was highly toxic, causing side effects and, in some cases, death.

NAFLD is the term used when there is a build-up of fat within the liver cells that is not caused by alcohol intake. It is usually seen in people who are overweight or obese, and is associated with metabolic syndrome. A healthy liver should contain little or no fat. Most people with NAFLD do not develop serious liver problems and just have stage 1 of the disease (simple fatty liver). The most important thing that people with NAFLD can do is to go on a gradual weight loss programme and exercise regularly.

It is known that DNP has benefits on NAFLD, obesity and regulating blood glucose, but is usually too toxic to be used as a treatment. The chemical targets the mitochondria in cells. These are the little "batteries" responsible for making energy in cells, which is essential for life.

DNP speeds up the metabolism; however, our metabolic system operates at the rate it does for a reason - it is safe. Speeding up the metabolism may help burn off fat, but it can also trigger a number of dangerous side effects and potentially cause death.

This research team tried to devise a way to harness the benefits of DNP, while minimising its toxic side effects. All their experiments were in rats. This is the usual approach when testing chemicals to treat diseases, particularly dangerous ones. People and rats, both mammals, share lots of common biology, but there are differences.

What did the research involve?

The researchers gave groups of rats low levels of DNP and monitored its effect on fat content in the liver and other measures linked to a higher risk of type 2 diabetes. They were looking to confirm the benefits reported in previous studies.

After encouraging results, they modified DNP to create CRMP (controlled-release mitochondrial protonophore). They fed this to rats in small amounts of peanut butter to see whether it had the same benefits, with fewer side effects.

The benefits and side effects of DNP were compared with CRMP in a range of experiments lasting up to six weeks. During the experiments, rats were fed a high-fat diet and the researchers paid particular attention to changes in the function of the liver in dealing with this fat.

What were the basic results?

The main result was that CRMP caused fewer side effects than raw DNP, while maintaining similar benefits, including burning lots of fat, improved glucose tolerance and lower insulin levels.

When testing for specific effects, CRMP prevented the development of the rat version of NAFLD in rats fed a high-fat diet for two weeks. Similarly, it seemed to improve blood glucose regulation when given to rats with diabetes for two weeks, also improving their blood fat levels.

CRMP released the DNP-active chemical at a more gradual rate, and over a longer period, than giving straight DNP. This meant the levels in the blood did not spike as much and were lower overall. This seems to be the key to avoiding some of the worst side effects.

One of the biggest side effects of DNP was that it caused a potentially fatal very high temperature. The researchers were able to find a dose of CRMP that was beneficial to the liver, without causing a huge rise in temperature.

How did the researchers interpret the results?

The researchers said: "we have shown that altering the pharmacokinetics of DNP to promote a low sustained systemic release can increase the therapeutic window of this agent by more than 500-fold. Daily CRMP administration reversed NAFLD, insulin resistance, T2D [type 2 diabetes], and liver fibrosis in rats without detectable toxicity".

They added: "These data support the potential utility of mitochondrial protonophores and other mitochondrial uncoupling agents for the treatment of the related epidemics of NASH, metabolic syndrome and T2D."

Conclusion

This study created a slow release version of DNP, called CRMP, that improved the way the liver processed fat and improved other measures linked to type 2 diabetes risk in rats. It did this when given for up to six weeks without the toxic side effects known to be associated with unmodified DNP.

This is encouraging research, which appears to have partially tamed some of the toxic effects of DNP, while protecting its benefits. Researchers will build on this in further studies in rats and possibly people, if these results are confirmed in more studies.

However, the current version of DNP that is available for sale illegally online is toxic to humans, even in tiny amounts, and has been linked to a number of deaths. Do not take it under any circumstances.

The study used a chemically-modified version of DNP, called CRMP, in rats. DNP on its own remains as dangerous as ever to people. CRMP's safety in humans has not yet been tested.

This study showed proof of the concept that DNP can be modified to make it safer in rats, while maintaining its benefits. This has not yet been proven in humans.

The authors are planning further safety studies, reporting in the Telegraph that: "Given these promising results in animal models of fatty liver disease and type 2 diabetes, we are pursuing additional preclinical safety studies to take this approach to the clinic."

Summary

"A chemical [DNP] which caused munitions factory workers to lose weight inexplicably in the First World War could cure diabetes," The Daily Telegraph reports. The banned weight loss drug looked effective and safe when given in a modified form to rats.